Project Summary The implantable cardioverter defibrillator (ICD) is the most effective means of detecting and treating arrhythmias, such as ventricular tachycardia (VT) or ventricular fibrillation (VF). However, despite its rapid acceptance, current ICD technology employs high-energy shocks that aim to terminate an arrhythmia only after the arrhythmia has started, therefore poses an immediate risk of fatality, pain associated with high-energy cardioversion and myocardial damage. It is imperative that the next generation of arrhythmia treatment technology is able to prevent arrhythmias from starting, rather than terminating them after their initiation. Repolarization alternans (RA) is a pattern of variation in the shape of electrocardiographic waveform that appears on an every other beat basis. Repolarization alternans has been associated with increased vulnerability to VT/VF and sudden cardiac death (SCD). In this paradigm-shift R21 grant application, we propose to investigate the hypothesis that vagal nerve stimulation before an abnormal heart rhythm develops may help prevent VT/VF and SCD. We have developed a prototype system that can estimate RA in real-time from intracardiac electrograms. Our team has also extensive experience in implanting vagal nerve stimulators in humans with heart failure. This proposal seeks to build upon our understanding of vagal nerve stimulation mechanisms in treating heart failure patients as well as in developing advanced algorithms aiming to prevent the onset of ventricular tachy-arrhythmias. Specifically, we will investigate the applicability of RA-triggered delivery of vagal nerve stimulation to suppress/terminate RA and prevent the development of VT/VF in an animal model of increased susceptibility of VT/VF. To achieve the aims of this proposal we will (i) assess the effect of vagal nerve stimulation on ventricular repolarization in-vivo; (ii) determine the efficacy of timely delivered vagal stimulation in reducing/suppressing repolarization alternans and preventing the onset of ventricular tachyarrhythmias. Success of this proposal will help develop a novel mechanistic paradigm that is specific to individual myocardial properties upon which custom, and more effective therapies may be adopted.